Pulmonary cytomegalovirus reactivation causes pathology in immunocompetent mice*

Cook, Charles H.; Zhang, Yingxue; Sedmak, Daniel D.; Martin, Ludmila Katherine; Jewell, Scott D.; Ferguson, Ronald M.

doi:10.1097/01.ccm.0000201876.11059.05

Cited by 79 publications

(97 citation statements)

References 48 publications

(62 reference statements)

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“…At first blush, this might not seem important in the case of the immunocompetent host, where CMV reactivation has not been previously considered to be pathogenic. Recently published work from our group, however, has shown that CMV reactivation is injurious in this setting (13), and this pathology might explain the increased morbidity seen in critically ill patients who suffer CMV reactivation.…”

Section: Discussionmentioning

confidence: 82%

Lipopolysaccharide, Tumor Necrosis Factor Alpha, or Interleukin-1β Triggers Reactivation of Latent Cytomegalovirus in Immunocompetent Mice

Cook

Trgovcich

Zimmerman

et al. 2006

J Virol

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124

122

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We have previously shown that cytomegalovirus (CMV) can reactivate in lungs of nonimmunosuppressed patients during critical illness. Our recent work has shown that polymicrobial bacterial sepsis can trigger reactivation of latent murine CMV (MCMV). We hypothesize that MCMV reactivation following bacterial sepsis may be caused by inflammatory mediators. To test this hypothesis, BALB/c mice latently infected with Smith strain MCMV received sublethal intraperitoneal doses of lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF-␣), interleukin-1␤ (IL-1␤), or saline. Lung tissue homogenates were evaluated for viral reactivation 3 weeks after mediator injection. Because LPS is known to signal via Toll-like receptor 4 (TLR-4) in mice, further studies blocking this signaling mechanism were performed using monoclonal MTS510. Finally, mice were tested with intravenous TNF-␣ to determine whether this would cause reactivation. All mice receiving sublethal intraperitoneal doses of LPS, TNF-␣, or IL-1␤ had pulmonary reactivation of latent MCMV 3 weeks following injection, and LPS caused MCMV reactivation with kinetics similar to those for sepsis. When TLR-4 signaling was blocked, exogenous LPS did not reactivate latent MCMV. Intravenous TNF-␣ administration at near-lethal doses did not reactivate MCMV. Exogenous intraperitoneal LPS, TNF-␣, and IL-1␤ are all capable of reactivating CMV from latency in lungs of previously healthy mice. LPS reactivation of MCMV appears dependent on TLR-4 signaling. Interestingly, intravenous TNF-␣ did not trigger reactivation, suggesting possible mechanistic differences that are discussed. We conclude that inflammatory disease states besides sepsis may be capable of reactivating CMV from latency.

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Section: Discussionmentioning

confidence: 82%

Lipopolysaccharide, Tumor Necrosis Factor Alpha, or Interleukin-1β Triggers Reactivation of Latent Cytomegalovirus in Immunocompetent Mice

Cook

Trgovcich

Zimmerman

et al. 2006

J Virol

Self Cite

124

122

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“…Herpesviruses may contribute to lung fibrosis by affecting lung inflammation. Latent herpesvirus infection has been associated with elevated levels of proinflammatory cytokines in humans and in animal models (2,17). MHV-68-infected IFN␥R-deficient mice, which progress to a fibrotic phenotype, have more inflammatory cells, higher levels of proinflammatory cytokines, and delayed resolution of inflammation compared with MHV-68-infected wild-type controls (23,24), a pattern also seen with MHV-68-infected/FITC-treated wild-type mice (20,34).…”

Section: Potential Mechanismsmentioning

confidence: 78%

Right place, right time: the evolving role of herpesvirus infection as a “second hit” in idiopathic pulmonary fibrosis

Kropski

Lawson

Blackwell

2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…For instance, studies conducted over a decade ago with rabbits (5), rats (86), dogs (19), pigs (68), and humans (4) indicate that circulating levels of VIP increase substantially in response to sepsis or endotoxemia. Septic shock or endotoxemia is also linked to murine CMV and HCMV reactivation in mice (13,14) and humans (26,43,80), respectively. VIP levels are also elevated in persons suffering from inflammatory bowel disease (16,32), another medical condition in which HCMV reactivates with greater frequency (33,51), even in the absence of immunosuppressive therapy (40).…”

Section: Discussionmentioning

confidence: 99%

Breaking Human Cytomegalovirus Major Immediate-Early Gene Silence by Vasoactive Intestinal Peptide Stimulation of the Protein Kinase A-CREB-TORC2 Signaling Cascade in Human Pluripotent Embryonal NTera2 Cells

Yuan

Liu

et al. 2009

J Virol

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. We speculate that neurohormonal stimulation via this signaling cascade is a possible means for reversing HCMV silence in vivo.Persons with impaired cellular immunity risk tissue-invasive disease from reactivation of latent human cytomegalovirus (HCMV). HCMV reactivation in tissues or blood of immunocompetent patients suffering illness from another cause also occurs but usually goes unnoticed and is self-limiting. For instance, nearly one-third of patients who are critically ill or in septic shock have detectable findings of HCMV reactivation in their bloodstream (12,26,43,45,80). HCMV reactivation infection in intestinal tissues with preexisting inflammatory disease (e.g., inflammatory bowel disease) is also well described for immunocompetent patients (28,39,40,51). The precise triggering mechanisms that underlie HCMV reactivation are unknown.So far, only cells of myeloid lineage have been determined to fulfill criteria for cellular sites of HCMV latency in vivo. In healthy HCMV-seropositive persons, precursors of macrophages and dendritic cells, including CD34ϩ hematopoietic progenitor cells, carry latent HCMV genomes at a low frequency (75). The terminal differentiation of these cells into a macrophage-or dendritic cell-like phenotype is a prerequisite for HCMV reactivation ex vivo (67, 76). However, this reactivation appears to be a rare event, suggesting that other, as yet unidentified factors may promote HCMV reactivation. Stimulation with tumor necrosis factor alpha (TNF-␣) or gamma interferon may promote HCMV reactivation from differentiated counterparts of monocytic-dendritic cell precursors that had been infected latently in vitro or in vivo (25,66,67,76).For both HCMV and murine CMV, viral major immediateearly (MIE) gene expression is greatly restricted or shut off during viral latency, and the productive viral life cycle cannot advance without this expression (57,74,75,78). The MIE enhancer/promoter controlling expression is regulated by the coordinated actions of multiple types of cis-acting elements (57). These elements are bound by cellular transcription factors whose functions are modulated by input supplied by the cell, the virus, and the external surrounding (57). Higher-order chromatin structure contributes to this regulation. Heterochromatin components amass on the inactive MIE enhancer/promoter in viral latency, whereas the chromatin signatures of transcriptional activity predominate at the active MIE enhancer/ promoter in acute and reactivation infections (47,67). MIE enhancer/promoter silencing is also favored by innate antiviral mechanisms that partly involve the repressive actions of nuclear ND10 domain components (e.g., hDAXX, PML, ATRX, and histone deacetylase [HDAC]) (52) but does not involve CpG methylation of the MIE enhancer/promoter (29).Quiescent HCMV infection of human NTera2/D1 cells (NT2 cells) is a tractable model system for studying the regulation of HCMV MIE enhancer/promoter reactivation (37, 54). NT2 cells share many phenotypic features with pluripotent

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Pulmonary cytomegalovirus reactivation causes pathology in immunocompetent mice*

Cited by 79 publications

References 48 publications

Lipopolysaccharide, Tumor Necrosis Factor Alpha, or Interleukin-1β Triggers Reactivation of Latent Cytomegalovirus in Immunocompetent Mice

Lipopolysaccharide, Tumor Necrosis Factor Alpha, or Interleukin-1β Triggers Reactivation of Latent Cytomegalovirus in Immunocompetent Mice

Right place, right time: the evolving role of herpesvirus infection as a “second hit” in idiopathic pulmonary fibrosis

Breaking Human Cytomegalovirus Major Immediate-Early Gene Silence by Vasoactive Intestinal Peptide Stimulation of the Protein Kinase A-CREB-TORC2 Signaling Cascade in Human Pluripotent Embryonal NTera2 Cells

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